6d78
The complex between high-affinity TCR DMF5(alpha-D26Y,beta-L98W) and human Class I MHC HLA-A2 with the bound MART-1(27-35)peptide
Structural highlights
FunctionMAR1_HUMAN Involved in melanosome biogenesis by ensuring the stability of GPR143. Plays a vital role in the expression, stability, trafficking, and processing of melanocyte protein PMEL, which is critical to the formation of stage II melanosomes.[1] [2] Publication Abstract from PubMedT cell receptors (TCRs) have emerged as a new class of immunological therapeutics. However, though antigen specificity is a hallmark of adaptive immunity, TCRs themselves do not possess the high specificity of monoclonal antibodies. Although a necessary function of T cell biology, the resulting cross-reactivity presents a significant challenge for TCR-based therapeutic development, as it creates the potential for off-target recognition and immune toxicity. Efforts to enhance TCR specificity by mimicking the antibody maturation process and enhancing affinity can inadvertently exacerbate TCR cross-reactivity. Here we demonstrate this concern by showing that even peptide-targeted mutations in the TCR can introduce new reactivities against peptides that bear similarity to the original target. To counteract this, we explored a novel structure-guided approach for enhancing TCR specificity independent of affinity. Tested with the MART-1-specific TCR DMF5, our approach had a small but discernible impact on cross-reactivity toward MART-1 homologs yet was able to eliminate DMF5 cross-recognition of more divergent, unrelated epitopes. Our study provides a proof of principle for the use of advanced structure-guided design techniques for improving TCR specificity, and it suggests new ways forward for enhancing TCRs for therapeutic use. Improving T Cell Receptor On-Target Specificity via Structure-Guided Design.,Hellman LM, Foley KC, Singh NK, Alonso JA, Riley TP, Devlin JR, Ayres CM, Keller GLJ, Zhang Y, Vander Kooi CW, Nishimura MI, Baker BM Mol Ther. 2019 Feb 6;27(2):300-313. doi: 10.1016/j.ymthe.2018.12.010. Epub 2018, Dec 14. PMID:30617019[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
| ||||||||||||||||||
